Nu-phenyl-2-substituted phenylamino-1, 4-naphthoquinoneimine compounds and methods of preparing the same



Patented July 20, 1954 N-PHENYL-2- SUBSTITUTED PHENYLAMINO-1,4-NAPHTHOQUINONEIMIN E COMPOUNDS AND METHODS OF PREPARING THE SAMERobert G. Shepherd and Jackson P. English,

Stamford, Conn., assignors to American Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Application March 27, 1951,

Serial No. 217,882

6 Claims. (01. 26 i-'396) This invention relates to new N-phenyl-2-(substituted phenylamino) 1,4 naphthoquinoneimines, their addition saltswith acids and methods of preparing the same. The new compounds of thisinvention, when in the form of their free bases, may be represented bythe following structural formula:

in which R. represents a lower dialkylamino substituent. The newnaphthoquinoneimines may be isolated in the form of their free bases andas such are crystalline compounds soluble in most common organicsolvents. Of course, the new compounds may also be prepared in the formof their acid addition salts, for instance as the hydrochloride,nitrate, or citrate. When in the form of their free bases, the newcompounds are red-violet dyes and in the form of their acid additionsalts they are green-blue dyes.

The new compounds of this invention, whether in the form of their freebases or in the form of their acid addition salts, show high activityagainst tubercle bacilli. While the exact nature of the activity is notfully understood, it is known that the activity is greatly influenced bythe variation of the group represented by R in the above structuralformula. This substituent must be a lower dialkylamino group, forinstance dimethylamino, methylethylamino and dipropylamino. If R in theabove formula represents hydrogen or a substituent such as ethoxy andphenylamino, the compounds are much less active, if not completely so.

The following table is for the purpose of showing the critical nature ofthe substituent labeled R in the above structural formula. The tablerepresents the results of tests in which mice infected with a virulentstrain of tubercle bacilli were fed, beginning on the day of infection,a selected naphthoquinoneimine mixed with their food in an amount equalto 0.4% by weight of thefood for a period of fourteen days after whichtreatment was discontinued. The median survival time of the mice sotreated was calculated and is as given in the table. The virulence ofthe infection was such that the untreated controls had a median survivaltime of fourteen days.

R Median Survival Time I N(C2H5)2 24 days. H Less than 18 days.

Do. Do.

Controls 14 days.

1 As an increase of three days or less in median survival time is smallenough that it might conceivably be attributed to other factors,compounds showing no more than this were simply marked I11- activeintestreports.

It should not be inferred from the above tests that thenaphthoquinoneimines are only effective in the amounts there employed.In fact, more beneficial results are usually obtained if the newcompounds are employed in increased amounts. It should likewise not beinferred that treatment should be discontinued after a certain period oftime as was done in the tests. No toxic efiects of the new compoundshave been observed and they may be employed for as long a period asdesired.

The new compounds of the present invention offer advantages over theantibiotics now commonly employed against tubercle bacilli infections inthat they are orally administered. Also, there has been no tendencyobserved for the new compounds to cause the development of drugresistant strains.

While it is intended that this invention cover the new compoundsregardless of how they are prepared, a particularly convenient method ofpreparing the new compounds has been discovered and this method alsoconstitutes a part of this invention. The new method comprises reactinga 4-ani1ino-1,2-naphthoquinone with the appropriately substitutedaniline compound as illustrated by the following equation:

in which R is as defined above.

The reaction is preferably performed in an organic solvent such asillustrated by the following: aliphatic alcohols, for instance ethanolor butanol; and cyclic others, for instance dioxane. The reaction may beperformed within a wide range of temperatures, for instance 60 to 130C., with the preferred range being 100 to 120 C. The reactants should beheated together for at least one hour and in some cases as long astwenty-four hours if high yields are desired.

The invention will be more particularly illustrated by means of thefollowing examples in which all parts are by weight unless otherwiseindicated.

EXAMPLE N -phenyZ-2- (p-diethylaminophenylamino) 1 ,4-naphthoquinoneimine Seven and one-half parts of lanilino-l,2-naphthoquinone and 6 parts of p-diethylamino aniline hydrochloride areadded to 3 parts of triethylamine and 100 parts by volume of n-butanol.The mixture is heated under reflux for two hours, cooled, and theseparated solid filtered. This material is crystallized from a largevolume of heptane to give purifiedN-pheny1-2-(p-diethylaminophenylamino) -1,4-naphthoquinoneimine.

Other naphthoquinoneimines of this invention are prepared bysubstantially the same procedure. For instance, in place of thep-diethylaminoaniline hydrochloride in the above example, one cansubstitute equal molar quantities of p-dimethylaminoanilinehydrochloride or p-dipropyh aminoaniline hydrochloride to produce N-pheny1- 2 (p e dimethylaminophenylamino) 1,4 naphthoquinoneimine andN-phenyl-2-(p-dipropylaminophenylamino) 1,4 naphthoquinoneiminerespectively.

We claim:

1. Compounds represented by the formula in which R1 and R2 representlower alkyl radicals.

by the formula in which R1 and R2 represent lower alkyl radicals whichcomprises reacting at a temperature of Gil-130 C.l-anilino-1,2-naphthoquinone with a compound represented by the formulain which R1 and R2 represent lower alkyl groups.

6. A method of making N-phenyl- 2 (p-diethylaminophenylamino) 1,4naphthoquinoneimine which comprises reacting at a temperature of C. toC. 4-anilino-l,2-naphthoquinone with p-diethylaminoaniline.

References Cited in the file of this patent UNITED STATES PATENTS NameDate Clifford Apr. 11, 1939 Number

1. COMPOUNDS REPRESENTED BY THE FORMULA